9-136410688-C-G

Variant names:

• chr9-136410688-C-G
• rs149055087
• NM_015160.3:c.20C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015160.3(PMPCA):​c.20C>G​(p.Ala7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: PMPCA NM_015160.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 7 publications found

Genes affected

PMPCA (HGNC:18667): (peptidase, mitochondrial processing subunit alpha) The protein encoded by this gene is found in the mitochondrion, where it represents the alpha subunit of a proteolytic heterodimer. This heterodimer is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins. Defects in this gene are a cause of spinocerebellar ataxia, autosomal recessive 2. [provided by RefSeq, Mar 2016]

ENTR1 (HGNC:10667): (endosome associated trafficking regulator 1) Involved in several processes, including endocytic recycling; positive regulation of cilium assembly; and positive regulation of protein localization to cilium. Located in endosome; microtubule organizing center; and midbody. Colocalizes with retromer complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108036876).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015160.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMPCA	NM_015160.3	MANE Select	c.20C>G	p.Ala7Gly	missense	Exon 1 of 13	NP_055975.1	Q10713-1
	PMPCA	NM_001282946.2		c.-279C>G		5_prime_UTR	Exon 1 of 13	NP_001269875.1
	PMPCA	NM_001282944.2		c.-279C>G		5_prime_UTR	Exon 1 of 12	NP_001269873.1	Q10713-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMPCA	ENST00000371717.8	TSL:1 MANE Select	c.20C>G	p.Ala7Gly	missense	Exon 1 of 13	ENSP00000360782.3	Q10713-1
	PMPCA	ENST00000622209.4	TSL:1	n.29C>G		non_coding_transcript_exon	Exon 1 of 5
	PMPCA	ENST00000444897.3	TSL:2	c.20C>G	p.Ala7Gly	missense	Exon 1 of 12	ENSP00000408393.2	Q5SXN9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 121318 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.92e-7 AC: 1 AN: 1261990 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 619818

African (AFR) AF: 0.00 AC: 0 AN: 25658

American (AMR) AF: 0.00 AC: 0 AN: 17892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19582

East Asian (EAS) AF: 0.00 AC: 0 AN: 30922

South Asian (SAS) AF: 0.00 AC: 0 AN: 55574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 9.83e-7 AC: 1 AN: 1017578

Other (OTH) AF: 0.00 AC: 0 AN: 50820

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 31

Bravo AF: 0.0000113

ExAC AF: 0.00000837 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.61
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.031
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.042	D
Polyphen		0.032	B
Vest4		0.28
MutPred		0.50		Loss of helix (P = 0.0072)
MVP		0.061
MPC		0.15
ClinPred		0.067	T
GERP RS		0.63
PromoterAI		-0.092	Neutral
Varity_R		0.058
gMVP		0.50
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149055087; hg19: chr9-139305140;